Influenza virus infection causes between three and five million cases of severe illness and between 250,000 and 500,000 deaths every year around the world. In the United States alone, 5% to 20% of the population becomes infected with influenza virus each year, with the majority of these infections caused by influenza A virus. (See, e.g., Dushoff et al., (2006) Am J Epidemiology 163:181-187; Thompson et al., (2004) JAMA 292:1333-1340; Thompson et al., (2003) JAMA 289:179-186.) Influenza B virus infections, however, account for approximately 10,000-100,000 hospitalized influenza cases per year in the United States alone, displaying a high year-to-year variability (1%-40% of all hospitalized influenza virus cases are influenza B virus infections, with a mean of 17%). (See Zhou et al (2012) Clin Inf Dis 54:1427-1436.) The burden associated with influenza virus infection on health care costs and lost productivity is extensive. Hospitalization and deaths mainly occur in high-risk groups, such as the elderly, children, and chronically ill.
Neuraminidase inhibitors are approved for outpatient treatment and prophylaxis for influenza A and B virus infection. TAMIFLU® oseltamivir phosphate is a widely used prophylactic and early therapeutic treatment option for influenza A and B virus infection. (See, e.g., Kandel and Hartshorn (2001) BioDrugs: Clinical Immunotherapy, Biopharmaceuticals and Gene Therapy 15:303-323; Nicholson et al., (2000) Lancet 355:1845-1850; Treanor et al., (2000) JAMA 283:1016-1024; and Welliver et al., (2001) JAMA 285:748-754.) However, oseltamivir treatment must begin within 48 hours of symptom onset to provide a significant clinical benefit. (See, e.g., Aoki et al (2003) J Antimicrobial Chemotherapy 51:123-129.) This liability compromises oseltamivir's ability to treat severely ill patients, who are typically beyond the optimal 48-hour treatment window at the time of seeking treatment. Additionally, oseltamivir is less effective at treating influenza B virus infection compared to treating influenza A virus infection, perhaps due in part to its 10-fold higher IC50 value for influenza B neuraminidase compared to that for influenza A neuraminidase. Therefore, significant focus has recently been placed on identifying influenza B virus therapeutics to treat hospitalized influenza B virus infected patients.
During 1988-1989, two highly distinct antigenic variants of influenza B virus emerged from ancestral influenza B virus lineages. These viruses were antigenically related to either influenza B virus B/Victoria/2/87 or B/Yamagata/16/88. (See, e.g., Rota et al. (1990) Virology 175:59-68.) It is therefore desirable to develop a therapy for influenza B virus infection that is effective against ancestral, Victoria, and Yamagata lineages of influenza B virus.
Recent reports have described monoclonal antibodies (mAb) that bind hemagglutinin and neutralize influenza B virus. (See Kubota-Koketsu et al. (2009) Biochem Biophys Res Comm 387:180-185; Yasugi et al. (2013) PLOS Pathogens 9:e1003150, 1-12; Dreyfus et al. (2012) Science Express 337:1343-1348; International application publication numbers WO 2013/007770, WO 2013/132007, WO 2013/114885, WO 2010/073647, and U.S. application publication numbers US 2009/0092620, US 2011/0319600, and US 2011/0319660.)
Despite these reports, a need still exists in the art for novel influenza B virus therapies effective against a broad range of influenza B virus strains, including influenza B virus therapies effective at treating or preventing influenza B virus infection of ancestral, Yamagata, and Victoria lineages. The present invention meets this need and provides other benefits for the treatment and prevention of influenza B virus infection.